Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
  • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
  • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
  • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/76—Unsaturated compounds containing keto groups
  • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
  • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings

Definitions

• the invention relates to new leukotriene-B 4 antagonists, process for their production as well as their use as pharmaceutical agents.
• Leukotriene B 4 (LTB 4 ) was discovered in 1979 by B. Samuelsson et al. as a metabolite of arachidonic acid. In the biosynthesis, leukotriene A 4 is formed by the enzyme 5-lipoxygenase first as a central intermediate product, which then is converted by a specific hydrolase to the LTB 4 .
• Leukotrien A 4 (LTA 4 ) leukotriene A 4 (LTA 4 )
• LTB 4 is an important inflammation mediator for inflammatory diseases, in which leukocytes invade the affected tissue.
• LTB 4 It is known from the LTB 4 that it causes the adhesion of leukocytes on the blood vessel wall.
• LTB 4 is chemotactically active, i.e., it triggers a directionally controlled migration of leukocytes in the direction of a gradient of increasing concentration. Further, because of its chemotactic activity, it indirectly changes the vascular permeability, and a synergism with prostaglandin E 2 is observed. LTB 4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
• Leukotrienes and especially LTB 4 are involved in skin diseases, which accompany inflammatory processes (increased vessel permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne.
• Pathologically increased leukotriene concentrations are involved either causally in the development of many dermatitides or there is a connection between the persistence of the dermatitides and the leukotrienes.
• Clearly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic dermatitis.
• leukotrienes and LTB 4 are involved especially in arthritis, chronic lung diseases (e.g., asthma), rhinitis and inflammatory intestinal diseases.
• Antagonists against LTB 4 itself or inhibitors of those enzymes which are involved in the synthesis of the LTB 4 can be effective as specific medications, especially against diseases which accompany inflammations and allergic reactions.
• the invention relates to leukotriene-B 4 antagonists of formula I ##STR5## in which
• X means a CH 2 group or an oxygen atom
• Y means C 1 -C 4 -alkoxy or --S(O) p --C 1 -C 4 -alkyl
• p 0, 1 or 2
• Z means a hydrogen atom or the radical A-B-COOH with A meaning a hydroxymethylene group or a carbonyl group and B meaning an alkylene group with 1-6 atoms in the chain or a radical ##STR6## with the exception that B does not mean the radical ##STR7## if X represents a CH 2 group, R 1 represents the radical OH, --O--(C 1 -C 4 )-alkyl, --O--(C 3 -C 6 )-cycloalkyl, --O--(C 6 -C 10 )-aryl, --O--(C 7 -C 12 )--aralkyl or the radical NR 4 R 6 with R 4 meaning hydrogen, (C 1 -C 4 )-(C 3 -C 6 )-cycloalkyl or (C 7 -C 12 )-aralkyl and R 6 meaning (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl
• Y and R 1 as the C 1 -C 4 -alkoxy group can mean: methoxy, ethoxy, n-propoxy, isoproxy, n-butoxy, sec.-butoxy and tert.-butoxy.
• alkylene group Z with 1-6 C atoms straight-chain or branched-chain saturated radicals are suitable, such as, e.g., methylene, ethylene, trimethylene, tetramethylene, hexamethylene, 1-methyltrimethylene, 1-methyl-tetramethylene, 1,1-diemthyltrimethylene etc.
• the radical (C 3 -C 6 )-cycloalkyl (for R 1 and R 4 ) can be: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• radicals C 6 -C 10 -aryl in the definition of R 1 phenyl, 1-naphthyl, 2-naphthyl are suitable.
• radicals C 7 -C 12 -aralkyl in the definitions of R 1 and R 4 represent the following groups: benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-methyl-3-phenylpropyl, 1-methyl-2-phenyl-ethyl, etc.
• Inorganic and organic bases as they are known to one skilled in the art for forming physiologically compatible salts are suitable for salt formation.
• alkali hydroxides such as sodium hydroxide and potassium hydroxide
• alkaline-earth hydroxides such as calcium hydroxide
• ammonia amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morphine, tris-(hydroxymethyl)-methylamine, etc.
• the compounds of formula I are reacted with ⁇ , ⁇ or ⁇ -cyclodextrin to achieve the cyclodextrin clathrates.
• the invention further relates to a process for the production of the leukotriene-B 4 antagonists of formula I, characterized in that, in a way known in the art, a compound of formula II ##STR8##
• R 5 means radicals OH or X--CH 2 --COOR, and X has the above-indicated meaning and R represents a C 1-C 4 -alkyl group, is reacted with a compound of formula III ##STR9## in which Y has the above-indicated meaning, in the presence of cesium carbonate, lithium carbonate or potassium carbonate and in case R 5 means the radical OH is reacted with a compound of formula IV
• the above-mentioned process (II+III-I) is performed in organic solvents, such as, e.g., dimethylformamide, at temperatures between 0° and 100° C., preferably at temperatures between 20° and 60° C. with stirring in the course of 5-24 hours in the presence of cesium carbonate, lithium carbonate or potassium carbonate.
• organic solvents such as, e.g., dimethylformamide
• the reduction of carbonyl group A preferably takes place with sodium borohydride under the usual conditions.
• the resulting hydroxymethylene compounds optionally can be separated in the optical antipodes.
• esters of formula I is performed according to the methods known to one skilled in the art, such as, for example, with basic catalysts.
• the 1-carboxy compounds are reacted, for example, with diazohydrocarbons in a way known in the art.
• the esterification with diazohydrocarbons takes place, e.g., in that a solution of diazohydrocarbon is mixed in an inert solvent, preferably in diethylether, with the 1-carboxy compound in the same or in another inert solvent, such as, e.g., methylene chloride. After completion of the reaction in 1 to 30 minutes the solvent is removed and the ester is purified in the usual way.
• Diazoalkanes are either known or can be produced according to known methods [Org. Reactions Vol. 8, pages 389-394 (1954)].
• ester group ##STR11## in which R 1 represents an --O---aryl group takes place according to methods known to one skilled in the art.
• the 1-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example, pyridine, DMAP, triethylamine, in an inert solvent.
• a suitable base for example, pyridine, DMAP, triethylamine
• solvent methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform, are suitable.
• the reaction is performed at temperatures between -30° C. and +50° C., preferably at 10° C.
• the leukotriene-B 4 antagonists of formula I with R 1 meaning a COOH group can be converted to a salt with suitable amounts of the corresponding inorganic bases with neutralization.
• the solid inorganic salt is obtained after evaporation of the water or after addition of a water-miscible solvent, e.g., alcohol or acetone.
• the LTB 4 acid e.g., is dissolved in a suitable solvent, for example, ethanol, acetone, diethyl ether, acetonitrile or benzene and at least the stoichiometric amount of the amine is added to this solution.
• a suitable solvent for example, ethanol, acetone, diethyl ether, acetonitrile or benzene
• the salt usually accumulates in solid form or is isolated after evaporation of the solvent in the usual way.
• the introduction of the amide group ##STR12## takes place according to methods known to one skilled in the art.
• the carboxylic acids of formula I (R 1 ⁇ OH) are first converted in the presence of a tertiary amine, such as, for example, triethylamine, with chloroformic acid isobutylester into the mixed anhydride.
• a tertiary amine such as, for example, triethylamine
• chloroformic acid isobutylester into the mixed anhydride.
• the reaction of the mixed anhydrides with the alkali salt of the corresponding amine or with ammonia takes place in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide at temperatures between -30° C. and +60° C., preferably at 0° C. to 30° C.
• the compounds of formula I act in an antiinflammatory and antiallergic manner. Consequently, the new leukotriene-B 4 derivatives of formula I represent valuable pharmaceutical active ingredients.
• the compounds of formula I are especially suitable for topical administration, since they exhibit a dissociation between desired topical effectiveness and undesirable systemic side effects.
• the new leukotriene-B 4 antagonists of formula I are suitable in combination with the auxiliary agents and vehicles usual in galenic pharmaceutics for topical treatment of contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, pruritus vulvae et ani, rosacea, cutaneus lupus erythematosus, psoriasis, lichen ruber planus et verrucosis and similar skin diseases.
• the production of the pharmaceutical agent specialties takes place in the usual way, by the active ingredients being converted with suitable additives to the desired form of administration, such as, for example: solutions, lotions, ointments, creams or plasters.
• the active ingredient concentration depends on the form of administration.
• an active ingredient concentration of 0.0001% to 1% is preferably used.
• the new compounds optionally in combination with the usual auxiliary agents and vehicles are also well-suited for the production of inhalants, which can be used to treat allergic diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
• the new leukotriene-B 4 antagonists are also suitable in the form of capsules, tablets or coated tablets, which preferably contain 0.1 to 100 mg of active ingredient or are administered orally or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dosage unit, and are also administered rectally to treat allergic diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
• the new leukotriene-B 4 derivatives can also be used in combination with, e.g., lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, prostaglandin agonists, thromboxane antagonists, leukotriene-D 4 antagonists, leukotriene-granulomatosa.
• a total of 49.6g of potassium-tert.-butylate is added in portions under argon at 0° C. to 97.7g of carboxybutyltriphenylphosphonium bromide in 205 ml of dimethylsulfoxide/108 ml of tetrahydrofuran and stirred for 1 hour at 0° C.
• 11.2g of 4-methoxybenzaldehyde dissolved in 200 ml of tetrahydrofuran is instilled and stirred for 2.5 hours at 50° C.
• 62.7g of methyliodide dissolved in 50 ml of tetrahydrofuran is instilled and stirred for 16 hours at 24° C.
• reaction mixture is poured on 800 ml of ice water, extracted three times each with 400 ml of methylene chloride, dried on sodium sulfate and concentrated by evaporation in a vacuum.
• the residue is purified by flash chromatography on silica gel with hexane/10-20% ethyl acetate. 15.8g of the title compound is obtained as colorless oil.
• IR 3005, 2958 , 2842 , 1730, 1608 , 1510, 1440, 1248 , 1175 , 1033, 968, 842 cm -1 .
• IR 3625, 3460, 3008, 2940, 2842, 1610, 1512, 1245, 1176, 1037, 968 cm -1 .
• IR 3000, 2970, 2938, 1610, 1512, 1438, 1247, 1105, 968 cm -1 .
• IR (KBr): 3510, 3300, 1740, 1700, 1640, 1590, 1579, 1440, 1318, 1240, 1120, 740, 715, 615 cm -1 .
• the reaction mixture is poured on ice/2n hydrochloric acid, shaken out with dichloromethane, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate (0-30% ethyl acetate).

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• 1990
  • 1990-09-07 DE DE4028866A patent/DE4028866A1/de not_active Withdrawn
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